PI3-Kinase (Phosphoinositide 3-Kinase, PI3K) is an enzyme responsible for the phosphorylation of hydroxyl group at the 3-position of the inositol ring of inositol phospholipid. Inositol triphosphate (PIP3) converted by PI3-Kinase activates AKT and the like and plays an important role in the growth, survival, motility and the like of a cell in response to extracellular signals (non-patent document 1).
PI3-Kinase is largely divided into Classes I, II and III based on its protein primary structure, of which Class I PI3-Kinase alone catalyzes a reaction from PIP2 as a substrate to PIP3. ClassI PI3-Kinase is further divided into Class IA (PIK3CA, PIK3CB, PIK3CD), and Class IB (PIK3CG). Among these, Class IA PI3-Kinase transmits growth or motility signals from a tyrosine kinase receptor to the downstream thereof, and Class IB PI3-Kinase is responsible for signal transduction from a G protein-conjugated receptor such as cytokine receptor and the like (non-patent document 2).
In addition, an enzyme (PTEN) responsible for a dephosphorylation reaction from inositol triphosphate (PIP3) to inositol diphosphate (PIP2) is defective due to various cancers (non-patent document 3), and PI3KCA is also reported to show active mutation in various cancers (non-patent documents 4, 5 and 6). Furthermore, an active mutant of PIK3CA can cancerate cells (non-patent documents 7 and 8).
Therefore, PI3-Kinase pathway is presumed to be highly frequently activated in cancer cells, and inhibition of PI3-Kinase is expected to lead a negative action on the growth, survival or motility of cancer. Accordingly, a PI3-Kinase inhibitor is expected to be a therapeutic drug for cancer.
On the other hand, signals of activated PI3-Kinase are transmitted to mTOR (mammalian Target of Rapamycin) molecule at the downstream via several molecules. This molecule forms two kinds of complexes (TORC1 and TORC2) having different functions depending on the two kinds of molecules (Raptor and Rictor) to be bonded (non-patent document 9). Rapamycin and analogs thereof suppress the activity of TORC1, but do not inhibit the activity of TORC2 (non-patent documents 9 and 10). Rapamycin analogs show a strong antitumor action clinically as well (non-patent documents 11 and 12), and inhibition of mTOR is also confirmed to be a promising target in cancer treatments. However, Rapamycin analogs are known to activate Akt molecule according to the status of IRS-1, since they inhibit TORC1 alone (non-patent document 13), and inhibition of not only PI3-Kinase but also mTOR is expected to show a strong antitumor action.    Non-Patent Document 1    Cantley, L. C., The Phosphoinositide 3-Kinase Pathway. Science. 296, 1655-1657 (2002)    Non-Patent Document 2    Wymann, M. P., and Pirola, L., Structure and function of phosphoinositide 3-Kinases. Biochim. Biophys. Acta 1436. 127-150 (1998)    Non-Patent Document 3    Li, J., et al., PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer. Science 275, 1943-1947 (1997)    Non-Patent Document 4    Lee, J. W., et al., PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene, 24, 1477-1480 (2005)    Non-Patent Document 5    Karakas, B., Bechman, K. E., and Park, B. H., Mutation of the PIK3CA oncogene in human cancers. British J. Cancer, 94, 455-459 (2006)    Non-Patent Document 6    Whyte, D. B., and Holbeck, S. L., Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. Biochem, Biophys. Res. Comm. 340, 469-475 (2006)    Non-Patent Document 7    Zhao, J. J., et al., The oncogenic properties of mutant p110a and p110b phosphatidilinositol 3-kinases in human mammary epithelial cells. Proc. Natl. Acad. Sci. USA, 102, 18443-18448 (2005)    Non-Patent Document 8    Bader, A. G., Kang, S., and Vogt, K., Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc. Natl. Acad. Sci. USA, 103, 1475-1479 (2006)    Non-Patent Document 9    Bhaskar P T, Hay N., The two TORCs and Akt. Dev. Cell. 12, 487-502 (2007)    Non-Patent Document 10    Wullschleger S, Loewith R, Hall M N., TOR signaling in growth and metabolism. Cell. 124, 471-84. (2006) Review.    Non-Patent Document 11    Garcia J A, Danielpour D., Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol Cancer Ther. 7, 1347-1354 (2008)    Non-Patent Document 12    Johnson B E, Jackman D, Jänne P A., Rationale for a phase I trial of erlotinib and the mammalian target of rapamycin inhibitor everolimus (RAD001) for patients with relapsed non small cell lung cancer. Clin Cancer Res. 13 (15 Pt 2): s4628-4631 (2007)    Non-Patent Document 13    Easton J B, Kurmasheva R T, Houghton P J., IRS-1: auditing the effectiveness of mTOR inhibitors. Cancer Cell. 9, 153-155. (2006)
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